Celastrol alleviates arthritis by modulating the inflammatory activities of neutrophils

Objective: Neutrophils play an important role in the pathogenesis of rheumatoid arthritis (RA). In this study, we used the adjuvant-induced arthritis murine model to evaluate the efficacy of celastrol on neutrophil-mediated inflammation in RA. Methods: Freund's complete adjuvant-induced arthritis was used as the murine model of RA. Celastrol was intraperitoneally administrated daily after onset of the disease. The joint diameter and inflammatory score were evaluated daily during the treatment period. Myeloperoxidase (MPO) and neutrophil elastase (NE) activities were evaluated by immunohistochemical analyses. Quantitative PCR and enzyme-linked immunoabsorbent assay were used to quantify the expression of cytokines. The expression of apoptosis-related proteins Bcl-2, Bax and caspase-3 were evaluated by western blot. Results: Celastrol suppressed inflammation in joints of arthritic mice and diminished the expression of MPO and NE in the joint tissue. Celastrol significantly inhibited the expression of TNFα and IL-6 induced by LPS in neutrophils in a dose-dependent manner in vitro. Moreover, celastrol induced apoptosis of LPS-stimulated neutrophils by increasing the expression of Bax and cleaved caspase-3 while decreasing Bcl-2 expression. Conclusion: Our findings show that celastrol significantly alleviates murine arthritis by modulating the inflammatory activities of neutrophils. These results indicate that celastrol could serve as an alternative or adjunct modality for the treatment of RA.